AlloStim® Immunotherapy Dosing Alone or in Combination With Cryoablation in Metastatic Colorectal Cancer

Phase 2

Completed

• Conditions: Colorectal Cancer Metastatic
• Interventions: Biological: AlloStim; Procedure: Cryoablation

• Registration Number: NCT02380443
• Lead Sponsor: Mirror Biologics, Inc.

Brief Summary

This is a single center, open label dose frequency escalation study of CryoVax®. personalized anti-tumor vaccine protocol combining the cryoablation of a selected metastatic lesion with intra-lesional immunotherapy with AlloStim®. The in-situ (in the body) cancer vaccine step combines killing a single metastatic tumor lesion by use of cryoablation in order to cause the release of tumor-specific markers to the immune system and then injecting bioengineered allogeneic immune cells (AlloStim®) into the lesion as an adjuvant in order to modulate the immune response and educate the immune system to kill other tumor cells where ever they reside in the body.

Detailed Description

Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Metastasis is the main reason of death in CRC patients. The current drugs used to treat colorectal cancer provide important treatment options for patients, their limitations including drug resistance, poor efficacy and severe side effects. Development of new therapeutic strategies for KRAS mutant as well as BRAF mutant tumors are therefore highly needed in order to offer a new category of drug (immunotherapy). This study targets the population of mCRC patients that have progressed after two lines of chemotherapy and are not eligible for targeted therapies. The study will assess six different dosing schedules. A standard 3 plus 3 study design will be used. The starting frequency for each dosing schedule will be escalated in subsequent groups of patients. The study will evaluate safety of increased frequency of AlloStim® dosing and anti-tumor effect of the new proposed dose and frequency schedule.

Study Timeline

• Study First Submitted: 2015-03-02
• Study First Submitted QC: 2015-03-04
• Study First Posted: 2015-03-05
• Study Start: 2016-09
• Status Verified: 2016-10
• Primary Completion: 2018-03
• Study Completion: 2018-09
• Last Update Submitted: 2020-01-17
• Last Update Posted: 2020-01-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

1. Adult males and female subjects aged 18-80 years at screening visit

2. Pathologically confirmed diagnosis of colorectal adenocarcinoma

3. Presenting with metastatic disease:

   • Primary can be intact or previously resected
   • Metastatic lesion(s) in liver must be non-resectable
   • Extrahepatic disease acceptable

4. At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation

5. Previous treatment failure of two previous lines of active systemic chemotherapy:

   • Previous chemotherapy must have included an oxaliplatin-containing (e.g. FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen
   • with or without bevacizumab
   • administered in adjuvant setting or for treatment of metastatic disease
   • If KRAS wild type, must have at least one prior anti-EGFR therapy
   • Treatment failure can be due to disease progression or toxicity
   • Disease progression on second line therapy must be documented radiologically and must have occurred during or within 30 days following the last administration of treatment for metastatic disease

6. ECOG performance score: 0-1

7. Adequate hematological function:

   • Absolute granulocyte count ≥ 1,200/mm3
   • Platelet count ≥ 100,000/mm3
   • PT/INR ≤ 1.5 or correctable to <1.5 at time of interventional procedures
   • Hemoglobin ≥ 9 g/dL (may be corrected by transfusion)

8. Adequate Organ Function:

   • Creatinine ≤ 1.5 mg/dL
   • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
   • Alkaline phosphatase ≤ 2.5 times ULN
   • Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN
   • Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN

9. EKG without clinically relevant abnormalities

10. Female subjects: Not pregnant or lactating

11. Patients with child bearing potential must agree to use adequate contraception

12. Study specific informed consent in the native language of the subject.

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Exclusion Criteria

1. Bowel obstruction or high risk for obstruction

2. Moderate or severe ascites requiring medical intervention

3. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal involvement

4. Symptomatic asthma or COPD

5. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room air

6. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation procedure

7. Regorafenib prior to the Study Period

8. Taking anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures)

9. Prior allogeneic bone marrow/stem cell or solid organ transplant

10. Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to > 5 mg/day of prednisone) within 30 days of the first day of study drug treatment

    • Topical corticosteroids are permitted

11. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed

12. Prior experimental therapy

13. History of blood transfusion reactions

14. Known allergy to bovine products

15. Progressive viral or bacterial infection

    • All infections must be resolved and the subject must remain afebrile for seven days without antibiotics prior to being placed on study

16. Cardiac disease of symptomatic nature

17. History of HIV positivity or AIDS

18. Concurrent medication known to interfere with platelet function or coagulation (e.g., aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications can be discontinued for an appropriate time period based on the drug half-life and known activity (e.g., aspirin for 7 days) prior to cryoablation and biopsy procedures

19. History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs

20. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation.

21. Subjects that lack ability to provide consent for themselves

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dosing Schedule A	AlloStim	* The priming step with ID injections of AlloStim on Days 0, 7, and 14 * The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 21 * The activation step with IV infusion of AlloStim on Day 28 * The booster step with two IV booster infusions of AlloStim on Days 56 and 84 Protocol follow-up procedures continue until day 112. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule B	AlloStim	* The priming step with ID injections of AlloStim on Days 0, 3 and days 7 and 10 * The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 14 * The activation step with IV infusion of AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule C	AlloStim	* The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 * IV AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule D (reducing dose)	AlloStim	The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 * IV AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule D (reducing dose)	Cryoablation	The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 * IV AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule A	Cryoablation	* The priming step with ID injections of AlloStim on Days 0, 7, and 14 * The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 21 * The activation step with IV infusion of AlloStim on Day 28 * The booster step with two IV booster infusions of AlloStim on Days 56 and 84 Protocol follow-up procedures continue until day 112. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule B	Cryoablation	* The priming step with ID injections of AlloStim on Days 0, 3 and days 7 and 10 * The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 14 * The activation step with IV infusion of AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up
Dosing Schedule C	Cryoablation	* The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 * IV AlloStim on Day 21 * The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Primary Outcome Measures

Name	Time	Method
To determine the safety of increased frequency of dosing (Part 1) (whether a Dose Limiting Toxicity (DLT) has occurred)	Window is defined from baseline until 28 days after the last dose administration ("Safety Evaluation Period")	Three patients are enrolled at each frequency schedule in the absence of dose limiting toxicity (DLT).Two types of toxicity are assessed for determination of whether a Dose Limiting Toxicity (DLT) has occurred. An acute dose limiting toxicity (ADLT) is assessed within 48h of a dose administration. Cumulative dose limiting toxicity (CDLT) is assessed during the complete Safety Evaluation Period.
To evaluate the anti-tumor effect of AlloStim combined with cryoablation at the new proposed dose and frequency schedule (Part 2)	28 days after last dose administration	Subjects at the new proposed dose and frequency schedule will be monitored for radiological, pathological and immunological response

Secondary Outcome Measures

Name	Time	Method
To assess change from baseline in Health-Related Quality of Life (HRQoL)	From enrollment to 28 days after last dose administration	Health-Related Quality of Life (HRQoL) will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)

Trial Locations

Locations (1)

Banner MD Anderson Medical Center; 🇺🇸 Gilbert, Arizona, United States